Duality and Complexity of Allergic Type Inflammatory Mechanisms in Determining the Outcome of Malaria Disease

One of the effector arms of the pathogenesis of severe forms of malaria disease is the development of uncontrolled or excessive inflammatory responses. A characteristic inflammatory response may arise from the propensity of some individuals to produce IgE antibodies against environmental antigens or against parasite components. We believe that an allergic inflammatory response which develops concomitantly with a malaria episode may drive the disease course toward severe forms. The role of the IgE–FcεRI complex in malaria severity in Plasmodium falciparum-hosting patients is unknown. Subsequently, except a very limited number of reports, study of effector cells that express this complex such as mast cells and basophils and that may contribute to malaria pathogenesis have been particularly neglected. A better understanding of this type of inflammatory response and its implication in malaria disease and how it impacts Plasmodium parasite development may provide additional tools to alleviate or to cure this deadly disease

Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease

From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC−/−) mice, which are free of histamine. HDC−/− mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC−/− mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC−/− mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria

Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria

FcεR1-expressing neutrophils accumulate in the brain of mice infected with Plasmodium berghei (PbANKA) and promote the development of experimental cerebral malaria

Asthma and atopic dermatitis are associated with increased risk of clinical<i>Plasmodium falciparum</i>malaria

OBJECTIVES: To assess the impact of atopy and allergy on the risk of clinical malaria. DESIGN: A clinical and immunological allergy cross-sectional survey in a birth cohort of 175 children from 1 month to 14 years of age followed for up to 15 years in a longitudinal open cohort study of malaria in Senegal. Malaria incidence data were available for 143 of these children (aged 4 months to 14 years of age) for up to 15 years. Mixed-model regression analysis was used to determine the impact of allergy status on malaria incidence, adjusting for age, gender, sickle-cell trait and force of infection. MAIN OUTCOME MEASURES: Asthma, allergic rhinoconjunctivitis and atopic dermatitis status, the number of clinical Plasmodium falciparum malaria episodes since birth and associated parasite density. RESULTS: 12% of the children were classified as asthmatic and 10% as having atopic dermatitis. These groups had respectively a twofold (OR 2.12 95%; CI 1.46 to 3.08; p=8×10(−5)) and threefold (OR 3.15; 1.56 to 6.33; p=1.3×10(−3)) increase in the risk of clinical P falciparum malaria once older than the age of peak incidence of clinical malaria (3–4 years of age). They also presented with higher P falciparum parasite densities (asthma: mean 105.3 parasites/μL±SE 41.0 vs 51.3±9.7; p=6.2×10(−3). Atopic dermatitis: 135.4±70.7 vs 52.3±11.0; p=0.014). There was no effect of allergy on the number of non-malaria clinical presentations. Individuals with allergic rhinoconjunctivitis did not have an increased risk of clinical malaria nor any difference in parasite densities. CONCLUSIONS: These results demonstrate that asthma and atopic dermatitis delay the development of clinical immunity to P falciparum. Despite the encouraging decrease in malaria incidence rates in Africa, a significant concern is the extent to which the increase in allergy will exacerbate the burden of malaria. Given the demonstrated antiparasitic effect of antihistamines, administration to atopic children will likely reduce the burden of clinical malaria in these children, increase the efficacy of first-line treatment antimalarials and alleviate the non-infectious consequences of atopy

Strain-Transcendent Immune Response to Recombinant Var2CSA DBL5-ε Domain Block P. falciparum Adhesion to Placenta-Derived BeWo Cells under Flow Conditions

BACKGROUND: Pregnancy-associated malaria (PAM) is a serious consequence of the adhesion to the placental receptor chondroitin sulfate A (CSA) of Plasmodium falciparum-infected erythrocytes (PE) expressing the large cysteine-rich multi-domain protein var2CSA. Women become resistant to PAM, and develop strain-transcending immunity against CSA-binding parasites. The identification of var2CSA regions that could elicit broadly neutralizing and adhesion-blocking antibodies is a key step for the design of prophylactic vaccine strategies. METHODOLOGY: Escherichia coli expressed var2CSA DBL domains were refolded and purified prior to immunization of mice and a goat. Protein-G-purified antibodies were tested for their ability to block FCR3(CSA)-infected erythrocytes binding to placental (BeWo) and monkey brain endothelial (ScC2) cell lines using a flow cytoadhesion inhibition assay mimicking closely the physiological conditions present in the placenta at shear stress of 0.05 Pa. DBL5-ε, DBL6-ε and DBL5-6-ε induced cross-reactive antibodies using Alum and Freund as adjuvants, which blocked cytoadhesion at values ranging between 40 to 96% at 0.5 mg IgG per ml. Importantly, antibodies raised against recombinant DBL5-ε from 3 distinct parasites genotypes (HB3, Dd2 and 7G8) showed strain-transcending inhibition ranging from 38 to 64% for the heterologuous FCR3(CSA). CONCLUSIONS: Using single and double DBL domains from var2CSA and Alum as adjuvant, we identified recombinant subunits inducing an immune response in experimental animals which is able to block efficiently parasite adhesion in a flow cytoadhesion assay that mimics closely the erythrocyte flow in the placenta. These subunits show promising features for inclusion into a vaccine aiming to protect against PAM

Arthropod Saliva and Its Role in Pathogen Transmission: Insect Saliva: Mosquito saliva, skin, allergy, and the outcome of Malaria infection - from mice to men

International audienceSkin provides the first line of defense against exoantigens including pathogens and allergens and is composed of a complex immune network that subsequently influences the systemic immune response. Arthropod saliva has profound effects on pathogen transmission, and the immunological response to saliva leads to both Type 1 and Type 4 hypersensitivity reactions, classically associated with allergic diseases. Such reactions result in immune deviation toward a Th2 response and a dysfunctional Th1 response, with significant consequences for the immune response to malaria and leishmaniasis parasites. In malaria, mast cells situated in the skin play a key role in linking these two responses producing histamine and thymic stromal lymphopoietin, master regulators of allergic inflammation. Increasing evidence from mouse models to natural infections in human populations provides support for considering the immune response to malaria within an allergic context and that saliva and its allergenic nature through direct response by immune effectors in the skin have significant immediate and long-term effects for the outcome of infection by malaria parasites and the development of clinical immunity. Together with tick saliva, sand fly saliva has been thoroughly investigated in numerous studies. It targets host pharmacology as well as its immune system. Sand fly salivary proteins act on different types of cells, including monocytes, neutrophils, dendritic cells, and lymphocytes. Therefore, these proteins modulate the innate immune response, leading to the production of mediators that favor the establishment of infection by Leishmania parasites. Besides that, it has been demonstrated that sand fly saliva induces apoptosis of neutrophils, increasing the parasite load in in vitro experiments. On the other hand, salivary proteins are immunogenic and induce humoral and cellular responses in mammalian hosts. These responses protect the host against an infection by Leishmania sp. because the delayed-type hypersensitivity response induced by after frequent exposure to bites, or by immunization with whole saliva or their proteins, creates an inhospitable environment that inhibits parasite growth. The robust protection against Leishmania conferred by immunity to several distinct salivary candidates suggests that their inclusion as part of a vaccine formulation may enhance its efficacy

A genetically hmgb2 attenuated blood stage P. berghei induces crossed-long live protection

International audienceDue to the lack of efficiency to control malaria elicited by sub-unit vaccine preparations, vaccination with live-attenuated Plasmodium parasite as reported 70 years ago with irradiated sporozoites regained recently a significant interest. The complex life cycle of the parasite and the different stages of development between mammal host and anopheles do not help to propose an easy vaccine strategy. In order to achieve a complete long-lasting protection against Plasmodium infection and disease, we considered a genetically attenuated blood stage parasite in the hmgb2 gene coding for the high-mobility-group-box 2 (HMGB2). This Plasmodium protein belongs to the HMGB family and hold as the mammal proteins, a double life since it acts first as a nuclear factor involved in chromatin remodelling and transcription regulation and second, when secreted as an active pro-inflammatory alarmin protein. Even though the number of reports on whole living attenuated blood stage parasites is limited when compared to attenuated sporozoites, the results reported with Plasmodium KO parasites are very encouraging. In this report, we present a novel strategy based on pre-immunization with Δhmgb2PbNK65 parasitized red blood cells that confer long-lasting protection in a murine experimental cerebral malaria model against two highly pathogenic homologous and heterologous parasites